Rheumatic diseases, such as arthritis, are characterized by inflammation and loss of function in one or more connecting or supporting structures of the body. Those structures, in particular, include: joints, tendons, ligaments, bones and muscles and in some cases internal organs. Some rheumatic diseases are classified as connective tissue disorders and include osteoarthritis, bursitis, spondyloarthropathies, fibromyalgia, gout, pseudogout, polymyositis, and tendonitis. Other rheumatic diseases are classified as autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, scleroderma, and psoriatic arthritis. While the pathogenesis of the diseases may vary, their characteristic inflammatory symptoms often share common inflammatory mediators.
Arthritis, the most common form of rheumatic diseases, is a group of diseases and disorders that afflict approximately 1% of the world's population. Arthritis is characterized by chronic inflammation of the joint, accompanied by pain, swelling and limitation of movement in joints and connective tissue. It afflicts more than 45 million people in the United States and is the leading cause of disability among adults age 65 and older. The most prevalent forms of arthritis are osteoarthritis and rheumatoid arthritis, both of them are progressive, degenerative diseases that lead to varying degrees of disability. The cartilage and bone of the joint undergo destruction with the progress of the disease, followed by loss of mobility, and increased suffering caused, among others, by the rubbing of bone against bone.
Osteoarthritis. Osteoarthritis (OA) is characterized by degradation of joints, including cartilage and bone. Symptoms include joint pain, stiffness, inflammation, tenderness and locking of joints. Nearly 27 million people in the United States are affected by OA with about a quarter of visits to primary care and 50% of all Non-Steroid Anti-Inflammatory prescriptions due to pain and lowered mobility from OA complications. Two types of osteoarthritis have been described, primary and secondary. Primary osteoarthritis is where the arthritis does not result from some other disorder, infection, or disease. Secondary osteoarthritis is where the arthritis is the result of another disorder, infection, or diseases, like diabetes, inflammatory diseases or hormonal disorders.
Rheumatoid arthritis. Rheumatoid arthritis (RA) is a rheumatic disease characterized by persistent synovial tissue inflammation. In time, this persistent inflammation can lead to bone erosion, destruction of cartilage, and complete loss of joint integrity. Eventually, multiple organs may be affected (Rindfleish et al. American Family Physician (2005), 72(6):103746). Joint damage is initiated by proliferation of synovial macrophages and fibroblasts after a triggering incident (for example, an autoimmune reaction or an infection). This is followed by infiltration of the perivascular regions by lymphocytes and endothelial cell proliferation, which leads to invasive tissue forming, growing irregularly and eventually invading and destroying cartilage and bone. The symptoms of rheumatoid arthritis include pain and stiffness affecting multiple joints. Symptoms can emerge over weeks and are often accompanied by anorexia, weakness, or fatigue. Joints most commonly affected are those with the highest ratio of synovium to articular cartilage, including the wrist and finger joints (Ruddy et al. eds. Kelly's Textbook of Rheumatology 7.sup.th ed. Philadelphia: W. B. Saunders, 2005:996-1042).
Gout. Gout is a form of acute arthritis, in which suffers have severe pain and swelling in joints. Gout often affects the heel, ankle, hand, wrist, elbow or big toe, and typically has a sudden onset. The symptoms of gout are characterized by the deposition of urate crystals in joint tissues as a result of urate supersaturation of extracellular fluids, a biochemical aberration reflected by hyperuricemia. Initially, however, patients suffer from asymptomatic hyperuricemia, meaning that these patients have elevated serum urate levels in their blood for a period of time before having their first gout attack. An acute attack of gout is manifested by a highly inflammatory arthritis that is often accompanied by intense swelling, redness and warmth surrounding a joint caused by the movement of monosodium urate crystals in or out of the cell. In addition, chills, a low grade fever and an elevated white blood cell count can occur, mimicking an infection. These acute attacks of gout are also referred to as “gout flares”. After an initial attack, a patient may go for a period of months or years without or between gout attacks. After a number of years of gouty attacks, patients may develop a chronic arthritis that results in bone and cartilage destruction and deformity. Urate crystals deposit within and surrounding the joint thereby causing a chronic destructive inflammatory process.
It is among the most common causes of acute monoarticular arthritis. In fact, estimates are that gout affects as many as 5 million Americans—twice the number of those affected with rheumatoid arthritis. While it is estimated that the overall incidence of gout among men and women is less than 1% (Pal, B., et al., Clin. Rheumatol., 19:21-25 (2000), Terkeltaub, R. A., N. Engl. J. Med., 349(17):1647-1655 (2003)), white males carry the major burden of this disease with a 8.6% cumulative incidence. (Roubenoff, R., et al., JAMA, 266:3004-3007 (1991)) In addition to gender, genetics also play a role in gout risk. Specifically, in the U.S., familial incidence of gout ranges from 6 to 18%. (Porter, R., Bull Hist. Med., 68:1-28 (1994)). Among hyperuricemic relatives of gout patients, the incidence of gout averages 20%. (Smyth, C. J., Metabolism, 6:218-229 (1957)).
Pseudogout. Pseudogout is similar in disease manifestation as gout, but it is not a hyperuremic disorder. Instead pseudogout involves the deposition of calcium pyrophosphate. Approximately 50% of the United States population above the age of 85 are affected by pseudogout.
Current treatments for arthritis (including: gout, RA, OA, and pseudogout) are colchicine, anti-inflammatory drugs, and glucocorticoids. The most effective of these, colchicine administered orally, cannot be tolerated by 80 percent of people because of side effects. There is a pronounced need in the art for economically-viable treatments for arthritis.